Flurbiprofen axetil emulsion for injection and preparation method thereof
A flurbiprofen axetil emulsion for injection can be prepared by specific stepwise addition of an oil phase to a water phase with shear mixing under the protection of nitrogen gas to obtain an emulsion. The oil phase includes flurbiprofen axetil, an oil phase solvent, an emulsifier, and a stabilizer, and the water phase includes water for injection and/or an osmotic pressure regulator. In the presence of a stabilizer in the oil phase, the emulsion can improve the emulsification effect by using the stepwise emulsifying technique for the oil phase, so that the obtained flurbiprofen axetil emulsion for injection has more uniform particle size, higher drug entrapment efficiency, and better targeting of the drug to the wounded tissue.
1. A method of preparation of a flurbiprofen axetil emulsion for injection, comprising:
adding 40 wt % to 60 wt % of an oil phase based on the total oil phase to a water phase with shear mixing under protection of nitrogen gas for 10 min to 30 min to obtain a crude emulsion A;
adding 20 wt % to 30 wt % of the oil phase based on the total oil phase to the crude emulsion A with shear mixing under the protection of the nitrogen gas for 10 min to 30 min to obtain a crude emulsion B; and
mixing the crude emulsion B with the rest of the total oil phase with shear mixing under the protection of the nitrogen gas for 10 min to 30 min to obtain an initial emulsion;
wherein the oil phase comprises flurbiprofen axetil, an oil phase solvent, an emulsifier, and a stabilizer, and
wherein the water phase comprises water for injection optionally an osmotic pressure regulator,
wherein the oil phase solvent is selected from the group consisting of a refined soybean oil, olive oil, medium-chain triglyceride, and a combination thereof,
wherein the emulsifier is selected from the group consisting of egg yolk lecithin, soybean lecithin, polyethylene glycol glyceryl stearate, and a combination thereof,
wherein the stabilizer is selected from the group consisting of dioleoylphosphatidylserine, dipalmitoylphosphatidic acid, sphingomyelin, and a combination thereof.
2. The method according to claim 1 , comprising:
wherein the crude emulsion A is obtained by adding 45 wt % to 55 wt % of the oil phase based on the total oil phase to the water phase with shear mixing under the protection of the nitrogen gas for 10 min to 20 min;
wherein the crude emulsion B is obtained by adding 20 wt % to 30 wt % of the oil phase based on the total oil phase to the crude emulsion A with shear mixing under the protection of the nitrogen gas for 10 min to 20 min; and
wherein the crude emulsion B is mixed with the rest of the total oil phase with shear mixing under the protection of the nitrogen gas for 20 min to 30 min.
3. The method according to claim 1 , wherein, the shear mixing speed is in the range of 4000 rpm to 10000 rpm.
4. The method according to claim 3 :
wherein the crude emulsion A is obtained with shear mixing at 4000 rpm to 6000 rpm;
wherein the crude emulsion B is obtained with shear mixing at 6000 rpm to 8000 rpm;
wherein the crude emulsion B is mixed with the rest of the total oil phase with shear mixing at 8000 rpm to 10000 rpm.
5. The method according to claim 1 , wherein the flurbiprofen axetil emulsion for injection comprises the following components: 1% to 2% of flurbiprofen axetil, 8% to 12% of an oil phase solvent, 1.0% to 1.5% of an emulsifier, 0.01% to 0.1% of a stabilizer, and the rest is water.
6. The method according to claim 1 , wherein the flurbiprofen axetil emulsion for injection includes 2.0% to 3.0% of the osmotic pressure regulator.
7. The method according to claim 6 , wherein the osmotic pressure regulator is one or two selected from the group consisting of glycerol, sucrose, and mannitol.
8. The method according to claim 1 , further comprising:
adjusting pH of the initial emulsion to 6.0 to 7.0,
homogenizing under a pressure of 60 Mpa to 100 Mpa and a temperature of 10° C. to 40° C. for 3 to 5 times to obtain a semi-finished product;
subjecting the obtained semi-finished product to filtration,
filling,
sealing and
sterilizing to obtain the flurbiprofen axetil emulsion for injection.
9. The method according to claim 1 , wherein the stabilizer is dioleoylphosphatidylserine.
10. The method according to claim 1 , wherein the emulsifier is egg yolk lecithin.
11. The method of preparation according to claim 1 , wherein the osmotic pressure regulator is selected from the group consisting of glycerol, sucrose, mannitol, and a combination thereof.